Long-Forgotten Research Unearths New Mystery About Lyme Disease

Introduction

On the top of a stack of documents in his garage was a mysterious note, penned boldly in red ink in the scientist’s unmistakable handwriting. “I wondered why somebody didn’t do something,” it said. “Then I realized that I am somebody.”

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Discovery sparks questions about factors that may make ailment harder to cure or lead to misdiagnosis.

A deer tick. Photo by U.S. Department of Agriculture

The tick hunter was hopeful he had found the cause of the disabling illness, recently named Lyme disease, that was spreading anxiety through leafy communities east of New York City. At a government lab in Montana, Willy Burgdorfer typed a letter to a colleague, reporting that blood from Lyme patients showed “very strong reactions” on a test for an obscure, tick-borne bacterium. He called it the “Swiss Agent.”

But further studies raised doubts about whether he had the right culprit, and 18 months later, in 1981, Burgdorfer instead pinned Lyme on another microbe. The Swiss Agent test results were forgotten.

Now STAT has obtained those documents, including some discovered in boxes of Burgdorfer’s personal papers found in his garage after his death in 2014. The papers—including letters to collaborators, lab records, and blood test results—indicate that the Swiss Agent was infecting people in Connecticut and Long Island in the late 1970s.

And scientists who worked with Burgdorfer, and reviewed key portions of the documents at STAT’s request, said the bacteria might still be sickening an unknown number of Americans today.

While the evidence is hardly conclusive, patients and doctors might be mistaking under-the-radar Swiss Agent infections for Lyme, the infectious disease specialists said. Or the bacteria could be co-infecting some Lyme patients, exacerbating symptoms and complicating their treatment—and even stoking a bitter debate about whether Lyme often becomes a persistent and serious illness.

Swiss Agent, now called Rickettsia helvetica, is likely not a major health risk in the United States, in part because such bacteria typically respond to antibiotics. Still, several of Burgdorfer’s former colleagues called for infectious disease researchers to mount a search for the bacterium.

“It should be done,” said Jorge Benach, a professor emeritus at Stony Brook University and a coauthor of Burgdorfer’s seminal 1982 paper describing the detection of the Lyme microbe. Public health concerns warrant a new study, Benach said, and with today’s more advanced “weaponry for pathogen discovery, it would make perfect sense.”

Dr. Paul Mead, chief of epidemiology and surveillance for the Centers for Disease Control and Prevention’s Lyme disease program, said that he wasn’t familiar with Rickettsia helvetica, but that “new tick-borne pathogens could certainly be out there.” He cited several found in the years since Lyme’s cause was discovered. Any serious, common co-infection would usually, but not always, be noticed by physicians as a distinct problem in Lyme endemic areas, he said.

In Europe and Asia, Rickettsia helvetica has been recognized as a relatively rare but sometimes serious health threat if untreated. It’s been linked to a handful of sudden deaths from heart disease, as well as facial palsy, deafness, meningitis, chronic muscle weakness, and temporary paralysis. But US laboratories don’t test for the Swiss Agent.

STAT was approached with Burgdorfer’s archives by Kris Newby, who is writing a biography of Burgdorfer and produced an award-winning documentary that sympathetically depicts Lyme patients and doctors who challenged the medical establishment over its approach to Lyme diagnosis and treatment.

The documents offer a tantalizing glimpse into how disease detectives tracked down Lyme’s cause—and how potentially significant loose ends can sometimes be dropped by researchers pressed for time and funding or diverted by more promising leads.

They show that Burgdorfer intended to look more deeply into the Swiss Agent, which he had discovered in 1978 in Switzerland, but never did. His former colleagues speculate that he set aside this research to focus on identifying the cause of Lyme. When the Swiss Agent turned out to be an unlikely candidate after all, he redeployed his limited time and resources to other prospects.

But the papers suggest that he might have gone to his grave harboring regret that he didn’t follow up on the Swiss Agent findings, as reasonable as the decision was, Benach said.

On the top of a stack of documents in his garage was a mysterious note, penned boldly in red ink in the scientist’s unmistakable handwriting. “I wondered why somebody didn’t do something,” it said. “Then I realized that I am somebody.”

The Lyme wars

Lyme has now become one of the most common infectious diseases in the United States—it’s been found in every state except Hawaii, and is rampant in the Northeast and parts of the Midwest. The CDC estimates that 329,000 people are infected annually.

Lyme has also provoked what’s often described as a “war” over diagnosis and treatment. If Rickettsia helvetica is in the United States, some experts consulted by STAT said, unrecognized infections might be one of several factors contributing to the controversy, by creating confusion over the cause of some patients’ illnesses.

The Infectious Diseases Society of America, the CDC, and many doctors view Lyme as generally easy to diagnose with its characteristic “bulls-eye” rash and pinpoint lab tests, and easy to cure with two-to-four weeks of antibiotics. If the disease is not diagnosed and treated early—in up to 30 percent of cases, there is no rash—patients can develop longer-lasting and more serious symptoms. But most infectious disease doctors say a short course of antibiotics will cure those patients.

But an insurgency of renegade doctors and patients disagrees. They argue that the diagnosis is frequently missed because of poor lab tests and other factors, and that Lyme becomes a chronic condition when untreated or inadequately treated. The patients describe symptoms that include incapacitating “brain fog” and weakness, intense anxiety, severe muscle pain, and paralyzing headaches. Many say that they required treatment with antibiotics lasting months or longer to be cured after years of misery.

Although the few small clinical trials that have examined long-term antibiotic therapy up to 90 days have shown few if any clear benefits, this camp has gained a passionate following, including a cadre of researchers who publish papers supporting this alternative view, and a medical group—the International Lyme and Associated Diseases Society.

The medical establishment mostly views “chronic Lyme” as the product of quack doctors exploiting desperate patients by offering unproven therapies. The patients sometimes need psychiatric care, these experts say, but in any case, chronic physical complaints are not caused by an active Lyme infection. Some state medical boards have gone so far as to revoke licenses of doctors who prescribe long-term antibiotics.

It’s hard to overstate the animosity that characterizes this clash. A few angry patients have compared establishment Lyme experts—including Dr. Allen Steere, who collaborated with Burgdorfer and has received death threats—to the Nazi doctor Joseph Mengele.

How might the Swiss Agent add fuel to this conflict? Steere, a Massachusetts General Hospital researcher and among the world’s leading Lyme experts, said some patients who believe they have Lyme, but who test negative for the infection, might be suffering from an illness caused by one of several other microbes. Rickettsia helvetica could be among them, he said.

Ticks often carry more than one pathogen, so patients can also have co-infections along with Lyme, which frequently begin with similar symptoms, such as fever, neck stiffness, and headaches.

“You can’t tell them apart clinically” in the first several weeks, Steere said. Co-infections can cause “more severe early disease … a phenomenon of the summer, when the tick bites.” Longer term, the confusion would not last because of Lyme’s distinct symptoms, even if the infection were untreated, he added.

Other experts noted that Lyme and Rickettsia helvetica have co-infected patients in Europe. Antibiotics normally cure Rickettsia helvetica infections, but diagnosis can prove difficult because the microbe does not cause a rash. If untreated or inadequately treated, the two infections share overlapping, serious, and sometimes persistent symptoms, according to clinical researchers. These include debilitating fatigue, severe headaches, muscle weakness, meningitis, facial paralysis, and sarcoidosis—a chronic inflammatory disease that can cause lung and skin problems. Numerous studies have linked Rickettsia helvetica to such ailments, although it is not regarded as a major public health peril in Europe.

Andrew Main, who conducted Lyme research at Yale University in collaboration with Steere and Burgdorfer, had Lyme early on, before its cause was discovered, and was among patients who showed evidence of co-infection with the Swiss Agent—a result that was included in Burgdorfer’s papers but that Main knew nothing about until informed by STAT. The positive tests for the Swiss Agent among Lyme patients back then, he said, strongly support the idea that it might be a current threat.

Robert Lane, a University of California, Berkeley, medical entomologist and Lyme expert who worked closely with Burgdorfer, is respected by both sides in the Lyme wars. He said Rickettsia helvetica could be a significant hidden factor that worsens Lyme infections and makes them harder to cure.

“You would want to look at it both ways. Could that organism, if present in some of the Lyme-disease endemic areas, infect people and cause clinical illness on its own, or react in concert with (the microbe that causes Lyme) or some of the other agents,” Lane said. “If you are looking for one or a few agents in a tick, you may be overlooking others that contribute to the disease burden.”

Finding the Swiss Agent

The man who found Lyme’s cause devoted his career to studying creatures sometimes described as tiny living cesspools, for the infectious stew of microbes ticks carry and transmit while sucking blood from animals or people.

While training for his PhD in his native Basel, Switzerland, Burgdorfer became a preeminent “tick surgeon,” as he called himself—dissecting thousands with eye scalpels and Swiss watchmaker forceps. In 1951 he became a research fellow at the federal Rocky Mountain Laboratories, a remote outpost in Montana’s breathtaking Bitterroot Valley that specializes in infectious agents.

Burgdorfer fell in love with the Bitterroot and with Gertrude Dale See—a secretary and technician at the lab. She won the multilingual scientist’s heart with her ability to speak French. They married and had two sons, and Burgdorfer became a US citizen and permanent lab employee.

He rose to lead the work on Rickettsia, rod-shaped bacteria spread by ticks that cause ailments such as Rocky Mountain Spotted Fever—which is sometimes deadly for patients in New England as well as the West. Burgdorfer built a global reputation for his knowledge of Rickettsia and Borrelia—corkscrew-shaped “spirochete” bacteria known for causing syphilis.

On a trip back to Switzerland in 1978, Burgdorfer and a few colleagues discovered in local ticks the previously unknown Swiss Agent—later named Rickettsia helvetica (from Switzerland’s ancient Latin name, Helvetia). He found the microbe infectious for meadow voles—a small rodent common in Europe and the United States—and deadly to chicken embryos. No one knew then that it also caused illnesses in people.

Burgdorfer returned with samples of infected ticks and Swiss Agent antigen, molecules from the bacterium that can provoke an immune response, for further study. When mixed with blood sera—a part of the blood that doesn’t contain blood cells—the antigen can show whether a person has been infected.

By then, Steere, a young Yale professor, had for several years been aggressively investigating why some of his patients in Lyme, Conn., were reporting serious and strange symptoms of an apparently new illness. He had found “that many patients suffered not only of arthritis, but also of disorders affecting the skin, muscular, cardiac, and nervous systems,” Burgdorfer told his official biographer from the National Institutes of Health in 2001.

Steere asked Burgdorfer to join the hunt for a tick-borne microbe believed to be at the heart of Lyme. He sent samples of his patients’ blood sera to Rocky Mountain Laboratories for analysis.

Sera tests showed that at least a dozen Lyme patients had been infected with Swiss Agent, and that at least six others might have been infected. The records did not make clear how many Lyme patients had been tested overall. Burgdorfer told Steere and other colleagues that the results pointed to a potential cause of Lyme.

Steere sensed a breakthrough. “I am excited to pursue further the possibility of a rickettsial etiology of Lyme disease,” he wrote to another researcher.

Burgdorfer was encouraged, in part, because of the test’s specificity: A positive result strongly suggested that the person had been infected with the Swiss Agent and not a different Rickettsia such as the one that causes Rocky Mountain Spotted Fever.

But when a second test method showed inconsistencies, doubts crept in about whether Swiss Agent was linked to Lyme. About 18 months later, Burgdorfer broke through, providing a rare undisputed fact in what would become the most disputatious of diseases: A spirochete causes Lyme. Years later, the microbe was named in his honor, Borrelia burgdorferi.

But he hadn’t given up on Swiss Agent completely.

In the lab during this period, Burgdorfer infected US ticks with the Swiss Agent, his lab books show. The records don’t state his experimental goal, but Rocky Mountain Lab scientists often studied which animals and arthropods could be infected with different agents, and thus might be reservoirs or vectors for disease. He also looked for Rickettsia in ticks in Lyme-endemic areas and found dozens of examples, but often neglected to determine the specific rickettsial species.

In December 1981, just a few months after discovering the Lyme spirochete, he wrote to a Swiss colleague who was overseeing a young investigator’s defense of his PhD thesis concerning the Swiss Agent. Burgdorfer suggested this question: “Do you feel that ‘Rickettsia suisse’ is the etiologic agent of (Lyme)? If so, how would you go about proving this?”

Burgdorfer and his colleagues reported their discovery of the cause of Lyme in the journal Science in 1982. In a handwritten draft found among Burgdorfer’s papers, he described identifying Rickettsia in Lyme patients’ sera and ticks, and his efforts to rule out Rickettsia as the cause of Lyme—without naming the Swiss Agent.

But in the final Science article, he made no mention of Rickettsia. Not a word about possibly finding the Swiss Agent in this country has ever been published.

Finishing the hunt

Burgdorfer retired in 1986 at age 60, just a few years after the successful Lyme hunt put him at the pinnacle of his field.

“I started to realize that the research I used to do and was successful in doing has changed its character,” he explained to a National Institutes of Health biographer in 2001. “Molecular and genetic biology have replaced the technologies I was able to apply,” he said. “Since I had no basic training in these fields … I was unable to speak and understand the completely new language.”

Those fluent in the “new language” of molecular biology and genetics will be able to finish Burgdorfer’s work, experts said. If the Swiss Agent is here, they can find it.

The CDC’s Mead said his agency is using molecular techniques to look for evidence of bacteria in 30,000 sera samples from people suspected to have contracted tick-borne illnesses. If Rickettsia helvetica is in some of the samples, it probably will be found, he said. That process will taken several more years to complete.

Dr. W. Ian Lipkin, who directs the Center for Infection and Immunity at Columbia University, is hunting for viruses as well as bacteria living in ticks that spread Lyme, partly to understand why antibiotics sometimes fail in apparent Lyme cases.

Lipkin’s group has collected 5,000 ticks from New York and Connecticut. With funding from the Steven and Alexandra Cohen Foundation, he has so far identified 20 new viruses in these ticks, and is exploring whether they have caused harmful infections in people, using tests that can search for a wide range of tick pathogens in a single sera sample. Eventually, Lipkin said, this process could make the tests affordable on a mass scale.

“Everyone wants to get to the bottom of this,” Lipkin said. “All of this is critical to … finding out why some people respond to antibiotics and some people don’t, and whether or not the antibiotics being used are appropriate, and trying to find ways to link different bacteria and different viruses to different syndromes.”

Lipkin is seeking funds to expand the work to tick-borne bacteria, including Rickettsia.

Asked whether his methods could find evidence of infections with the Swiss Agent, Lipkin replied without hesitation. “The answer is yes,” he said. “If this particular rickettsial species is present, I’m sure we will see it.”

Willy’s last words

After he retired, Burgdorfer sent most of his voluminous personal files to the National Archives in Washington, D.C., where they were cataloged for public viewing. Those records contained some Swiss Agent documents. Many more lay untouched for decades in his garage and home office in Hamilton, Mont.

Late in life, Burgdorfer developed Parkinson’s disease and became increasingly infirm. A friend listened to his fears that his garage files might be lost to history. She urged Burgdorfer to contact Ron Lindorf, then an entrepreneur and business professor at Brigham Young University, who had been suggested by colleagues.

Early one morning in June 2014, an agitated Burgdorfer called Lindorf with an urgent request: “Come to Montana and get all my research, my files. I want to put it on the internet so people can see it,” Lindorf recalled him saying.

Lindorf was not a professional archivist, but agreed: His children had suffered from serious bouts of Lyme disease, he was eager to help the scientist who discovered Lyme’s cause, and he had the ability to take on the complex job. The next month Lindorf arrived in Hamilton, departing two days later with his SUV packed full of old files. That November, Burgdorfer died.

To better understand the Burgdorfer archive, Lindorf began collaborating with Newby, producer of “Under Our Skin,” the Lyme documentary. She shared the documents with STAT, hoping that an independent report would illuminate a possibly hidden risk for Lyme patients and others.

Lindorf returned to Montana last year to visit Burgdorfer’s second wife. She pointed across the garage to some additional boxes. Inside a cardboard portfolio covered in flowery fabric and closed by a metal clasp, he found more of the Swiss Agent archives, topped by Burgdorfer’s “I wondered why somebody didn’t do something” note.

“It made the hairs on the back of my neck stick up,” Lindorf said. “It felt like Willy talking from the grave.”